Direct maternal morbidity and the risk of pregnancy-related deaths, stillbirths, and neonatal deaths in South Asia and sub-Saharan Africa: A population-based prospective cohort study in 8 countries.

BACKGROUND: Maternal morbidity occurs several times more frequently than mortality, yet data on morbidity burden and its effect on maternal, foetal, and newborn outcomes are limited in low- and middle-income countries. We aimed to generate prospective, reliable population-based data on the burden of major direct maternal morbidities in the antenatal, intrapartum, and postnatal periods and its association with maternal, foetal, and neonatal death in South Asia and sub-Saharan Africa. METHODS AND FINDINGS: This is a prospective cohort study, conducted in 9 research sites in 8 countries of South Asia and sub-Saharan Africa. We conducted population-based surveillance of women of reproductive age (15 to 49 years) to identify pregnancies. Pregnant women who gave consent were include in the study and followed up to birth and 42 days postpartum from 2012 to 2015. We used standard operating procedures, data collection tools, and training to harmonise study implementation across sites. Three home visits during pregnancy and 2 home visits after birth were conducted to collect maternal morbidity information and maternal, foetal, and newborn outcomes. We measured blood pressure and proteinuria to define hypertensive disorders of pregnancy and woman's self-report to identify obstetric haemorrhage, pregnancy-related infection, and prolonged or obstructed labour. Enrolled women whose pregnancy lasted at least 28 weeks or those who died during pregnancy were included in the analysis. We used meta-analysis to combine site-specific estimates of burden, and regression analysis combining all data from all sites to examine associations between the maternal morbidities and adverse outcomes. Among approximately 735,000 women of reproductive age in the study population, and 133,238 pregnancies during the study period, only 1.6% refused consent. Of these, 114,927 pregnancies had morbidity data collected at least once in both antenatal and in postnatal period, and 114,050 of them were included in the analysis. Overall, 32.7% of included pregnancies had at least one major direct maternal morbidity; South Asia had almost double the burden compared to sub-Saharan Africa (43.9%, 95% CI 27.8% to 60.0% in South Asia; 23.7%, 95% CI 19.8% to 27.6% in sub-Saharan Africa). Antepartum haemorrhage was reported in 2.2% (95% CI 1.5% to 2.9%) pregnancies and severe postpartum in 1.7% (95% CI 1.2% to 2.2%) pregnancies. Preeclampsia or eclampsia was reported in 1.4% (95% CI 0.9% to 2.0%) pregnancies, and gestational hypertension alone was reported in 7.4% (95% CI 4.6% to 10.1%) pregnancies. Prolonged or obstructed labour was reported in about 11.1% (95% CI 5.4% to 16.8%) pregnancies. Clinical features of late third trimester antepartum infection were present in 9.1% (95% CI 5.6% to 12.6%) pregnancies and those of postpartum infection in 8.6% (95% CI 4.4% to 12.8%) pregnancies. There were 187 pregnancy-related deaths per 100,000 births, 27 stillbirths per 1,000 births, and 28 neonatal deaths per 1,000 live births with variation by country and region. Direct maternal morbidities were associated with each of these outcomes. CONCLUSIONS: Our findings imply that health programmes in sub-Saharan Africa and South Asia must intensify their efforts to identify and treat maternal morbidities, which affected about one-third of all pregnancies and to prevent associated maternal and neonatal deaths and stillbirths. TRIAL REGISTRATION: The study is not a clinical trial.

Multiomics Characterization of Preterm Birth in Low- and Middle-Income Countries.

Importance: Worldwide, preterm birth (PTB) is the single largest cause of deaths in the perinatal and neonatal period and is associated with increased morbidity in young children. The cause of PTB is multifactorial, and the development of generalizable biological models may enable early detection and guide therapeutic studies. Objective: To investigate the ability of transcriptomics and proteomics profiling of plasma and metabolomics analysis of urine to identify early biological measurements associated with PTB. Design, Setting, and Participants: This diagnostic/prognostic study analyzed plasma and urine samples collected from May 2014 to June 2017 from pregnant women in 5 biorepository cohorts in low- and middle-income countries (LMICs; ie, Matlab, Bangladesh; Lusaka, Zambia; Sylhet, Bangladesh; Karachi, Pakistan; and Pemba, Tanzania). These cohorts were established to study maternal and fetal outcomes and were supported by the Alliance for Maternal and Newborn Health Improvement and the Global Alliance to Prevent Prematurity and Stillbirth biorepositories. Data were analyzed from December 2018 to July 2019. Exposures: Blood and urine specimens that were collected early during pregnancy (median sampling time of 13.6 weeks of gestation, according to ultrasonography) were processed, stored, and shipped to the laboratories under uniform protocols. Plasma samples were assayed for targeted measurement of proteins and untargeted cell-free ribonucleic acid profiling; urine samples were assayed for metabolites. Main Outcomes and Measures: The PTB phenotype was defined as the delivery of a live infant before completing 37 weeks of gestation. Results: Of the 81 pregnant women included in this study, 39 had PTBs (48.1%) and 42 had term pregnancies (51.9%) (mean [SD] age of 24.8 [5.3] years). Univariate analysis demonstrated functional biological differences across the 5 cohorts. A cohort-adjusted machine learning algorithm was applied to each biological data set, and then a higher-level machine learning modeling combined the results into a final integrative model. The integrated model was more accurate, with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% CI, 0.72-0.91) compared with the models derived for each independent biological modality (transcriptomics AUROC, 0.73 [95% CI, 0.61-0.83]; metabolomics AUROC, 0.59 [95% CI, 0.47-0.72]; and proteomics AUROC, 0.75 [95% CI, 0.64-0.85]). Primary features associated with PTB included an inflammatory module as well as a metabolomic module measured in urine associated with the glutamine and glutamate metabolism and valine, leucine, and isoleucine biosynthesis pathways. Conclusions and Relevance: This study found that, in LMICs and high PTB settings, major biological adaptations during term pregnancy follow a generalizable model and the predictive accuracy for PTB was augmented by combining various omics data sets, suggesting that PTB is a condition that manifests within multiple biological systems. These data sets, with machine learning partnerships, may be a key step in developing valuable predictive tests and intervention candidates for preventing PTB.

Provider performance and facility readiness for managing infections in young infants in primary care facilities in rural Bangladesh.

BACKGROUND: Neonatal infections remain a leading cause of newborn deaths globally. In 2015, WHO issued guidelines for managing possible serious bacterial infection (PSBI) in young infants (0-59 days) using simplified antibiotic regimens when compliance with hospital referral is not feasible. Bangladesh was one of the first countries to adopt WHO's guidelines for implementation. We report results of an implementation research study that assessed facility readiness and provider performance in three rural sub-districts of Bangladesh during August 2015-August 2016. METHODS: This study took place in 19 primary health centers. Facility readiness was assessed using checklists completed by study staff at three time points. To assess provider performance, we extracted data for all infection cases from facility registers and compared providers' diagnosis and treatment against the guidelines. We plotted classification and dosage errors across the study period and superimposed a locally weighted smoothed (LOWESS) curve to analyze changes in performance over time. Focus group discussions (N = 2) and in-depth interviews (N = 28) with providers were conducted to identify barriers and facilitators for facility readiness and provider performance. RESULTS: At baseline, none of the facilities had adequate supply of antibiotics. During the 10-month period, 606 sick infants with signs of infection presented at the study facilities. Classification errors were identified in 14.9% (N = 90/606) of records. For infants receiving the first dose(s) of antibiotic treatment (N = 551), dosage errors were identified in 22.9% (N = 126/551) of the records. Distribution of errors varied by facility (35.7% [IQR: 24.7-57.4%]) and infection severity. Errors were highest at the beginning of the study period and decreased over time. Qualitative data suggest errors in early implementation were due to changes in providers' assessment and treatment practices, including confusion about classifying an infant with multiple signs of infection, and some providers' concerns about the efficacy of simplified antibiotic regimens. CONCLUSIONS: Strategies to monitor early performance and targeted supports are important for enhancing implementation fidelity when introducing complex guidelines in new settings. Future research should examine providers' assessment of effectiveness of simplified treatment and address misconceptions about superiority of broader spectrum antibiotics for treating community-acquired neonatal infections in this context.

Caregiver acceptability of the guidelines for managing young infants with possible serious bacterial infections (PSBI) in primary care facilities in rural Bangladesh.

INTRODUCTION: Many infants with possible serious bacterial infections (PSBI) do not receive inpatient treatment because hospital care may not be affordable, accessible, or acceptable for families. In 2015, WHO issued guidelines for managing PSBI in young infants (0-59 days) with simpler antibiotic regimens when hospital care is not feasible. Bangladesh adopted WHO's guidelines for implementation in outpatient primary health centers. We report results of an implementation research study that assessed caregiver acceptability of the guidelines in three rural sub-districts of Bangladesh during early implementation (October 2015-August 2016). METHODS: We included 19 outpatient primary health centers involved in the initial rollout of the infection management guidelines. We extracted data for all PSBI cases (N = 192) from facility registers to identify gaps in referral feasibility, simplified antibiotic treatment, and follow-up. Focus group discussions (FGD) and in-depth interviews (IDI) were conducted with both caregivers (6 FGDs; 23 IDIs) and providers (2 FGDs; 28 IDIs) to assess caregiver acceptability of the guidelines. RESULTS: Referral to the hospital was not feasible for many families (83.3%; N = 160/192) and acceptance varied by infection severity. Barriers to referral feasibility included economic and household factors, and previous experiences with poor quality of care at the sub-district hospital. Conversely, providers and caregivers indicated high acceptability of simplified antibiotic treatment. 80% (N = 96/120) of infants with clinical severe infection for whom referral was not feasible returned to the facility for the second antibiotic injection. Some providers reported developing local solutions-including engaging informal providers in treatment of the infant-to address organizational barriers and promote treatment compliance. Follow-up of young infants receiving simplified treatment is critical, but only 67.4% (N = 87/129) of infants received fourth day follow-up. Some providers' reported deviations from the guidelines that shifted responsibility of follow-up to the caregiver, which may have contributed to lapses. CONCLUSION: Caregivers' perception of trust and communication with providers were influential in caregiver acceptability of care. Few caregivers accepted referral to the sub-district hospital, suggesting low acceptability of this option. When referral was not feasible, many caregivers reported satisfaction with simplified antibiotic treatment. Local solutions described by providers require further examination in this context to assess the safety and potential value of these strategies in outpatient treatment. Our findings suggest strengthening providers' interpersonal skills could improve caregiver acceptability of the guidelines.

Incidence and risk factors of neonatal infections in a rural Bangladeshi population: a community-based prospective study.

BACKGROUND: Infections cause about one fifth of the estimated 2.7 million annual neonatal deaths worldwide. Population-based data on burden and risk factors of neonatal infections are lacking in developing countries, which are required for the appropriate design of effective preventive and therapeutic interventions in resource-poor settings. METHODS: We used data from a community-based cluster-randomized trial conducted to evaluate the impact of two umbilical cord cleansing regimens with chlorhexidine solution on neonatal mortality and morbidity in a rural area of Sylhet District in Bangladesh. Newborns were assessed four times in the first 9 days of life by trained community health workers (CHWs) using a WHO IMCI-like clinical algorithm. Cumulative incidence of the first episode of infections in the first 9 days of life was estimated using survival analysis technique accounting for survival bias and competing risk of death before the occurrence of infection. A multivariable generalized estimating equation log-binomial regression model was used to identify factors independently associated with infections. RESULTS: Between 2007 and 2009, 30,267 newborns who received at least one postnatal assessment visit by a CHW within the first 9 days of life were included in this study. Cumulative incidence of infections in the first 9 days of life was 14.5% (95% CI 14.1-14.9%). Significant risk factors included previous child death in the family [RR 1.10 (95% CI 1.02-1.19)]; overcrowding [RR 1.14 (95% CI 1.04-1.25)]; home delivery [RR 1.86 (95% CI 1.58-2.19)]; unclean cord care [RR 1.15 (95% CI 1.03-1.28)]; multiple births [RR 1.34 (95% CI 1.15-1.56)]; low birth weight [reference: ≥ 2500 g, RR (95% CI) for < 1500, 1500-1999, and 2000-2499 g were 4.69 (4.01-5.48), 2.15 (1.92-2.42), and 1.15 (1.07-1.25) respectively]; and birth asphyxia [RR 1.65 (1.51-1.81)]. Higher pregnancy order lowered the risk of infections in the study population [compared to first pregnancy, RR (95% CI) for second, third, and ≥ fourth pregnancy babies were 0.93 (0.85-1.02), 0.88 (0.79-0.97), and 0.79 (0.71-0.87), respectively]. CONCLUSION: Neonatal infections and associated deaths can be reduced by identifying and following up high-risk mothers and newborns and promoting facility delivery and clean cord care in resource-poor countries like Bangladesh where the burden of clinically ascertained neonatal infections is high. Further research is needed to measure the burden of infections in the entire neonatal period, particularly in the second fortnight and its association with essential newborn care. TRIAL REGISTRATION: NCT00434408 . Registered February 9, 2007.

Understanding biological mechanisms underlying adverse birth outcomes in developing countries: protocol for a prospective cohort (AMANHI bio-banking) study.

OBJECTIVES: The AMANHI study aims to seek for biomarkers as predictors of important pregnancy-related outcomes, and establish a biobank in developing countries for future research as new methods and technologies become available. METHODS: AMANHI is using harmonised protocols to enrol 3000 women in early pregnancies (8-19 weeks of gestation) for population-based follow-up in pregnancy up to 42 days postpartum in Bangladesh, Pakistan and Tanzania, with collection taking place between August 2014 and June 2016. Urine pregnancy tests will be used to confirm reported or suspected pregnancies for screening ultrasound by trained sonographers to accurately date the pregnancy. Trained study field workers will collect very detailed phenotypic and epidemiological data from the pregnant woman and her family at scheduled home visits during pregnancy (enrolment, 24-28 weeks, 32-36 weeks & 38+ weeks) and postpartum (days 0-6 or 42-60). Trained phlebotomists will collect maternal and umbilical blood samples, centrifuge and obtain aliquots of serum, plasma and the buffy coat for storage. They will also measure HbA1C and collect a dried spot sample of whole blood. Maternal urine samples will also be collected and stored, alongside placenta, umbilical cord tissue and membrane samples, which will both be frozen and prepared for histology examination. Maternal and newborn stool (for microbiota) as well as paternal and newborn saliva samples (for DNA extraction) will also be collected. All samples will be stored at -80°C in the biobank in each of the three sites. These samples will be linked to numerous epidemiological and phenotypic data with unique study identification numbers. IMPORTANCE OF THE STUDY: AMANHI biobank proves that biobanking is feasible to implement in LMICs, but recognises that biobank creation is only the first step in addressing current global challenges.

Safety and efficacy of alternative antibiotic regimens compared with 7 day injectable procaine benzylpenicillin and gentamicin for outpatient treatment of neonates and young infants with clinical signs of severe infection when referral is not possible: a randomised, open-label, equivalence trial.

BACKGROUND: Severe infections remain one of the main causes of neonatal deaths worldwide. Possible severe infection is diagnosed in young infants (aged 0-59 days) according to the presence of one or more clinical signs. The recommended treatment is hospital admission with 7-10 days of injectable antibiotic therapy. In low-income and middle-income countries, barriers to hospital care lead to delayed, inadequate, or no treatment for many young infants. We aimed to identify effective alternative antibiotic regimens to expand treatment options for situations where hospital admission is not possible. METHODS: We did this randomised, open-label, equivalence trial in four urban hospitals and one rural field site in Bangladesh to determine whether two alternative antibiotic regimens with reduced numbers of injectable antibiotics combined with oral antibiotics had similar efficacy and safety to the standard regimen, which was also used as outpatient treatment. We randomly assigned infants who showed at least one clinical sign of severe, but not critical, infection (except fast breathing alone), whose parents refused hospital admission, to one of the three treatment regimens. We stratified randomisation by study site and age (<7 days or 7-59 days) using computer-generated randomisation sequences. The standard treatment was intramuscular procaine benzylpenicillin and gentamicin once per day for 7 days (group A). The alternative regimens were intramuscular gentamicin once per day and oral amoxicillin twice per day for 7 days (group B) or intramuscular procaine benzylpenicillin and gentamicin once per day for 2 days, then oral amoxicillin twice per day for 5 days (group C). The primary outcome was treatment failure within 7 days after enrolment. Assessors of treatment failure were masked to treatment allocation. Primary analysis was per protocol. We used a prespecified similarity margin of 5% to assess equivalence between regimens. This study is registered with ClinicalTrials.gov, number NCT00844337. FINDINGS: Between July 1, 2009, and June 30, 2013, we recruited 2490 young infants into the trial. We assigned 830 infants to group A, 831 infants to group B, and 829 infants to group C. 2367 (95%) infants fulfilled per-protocol criteria. 78 (10%) of 795 per-protocol infants had treatment failure in group A compared with 65 (8%) of 782 infants in group B (risk difference -1.5%, 95% CI -4.3 to 1.3) and 64 (8%) of 790 infants in group C (-1.7%, -4.5 to 1.1). In group A, 14 (2%) infants died before day 15, compared with 12 (2%) infants in group B and 12 (2%) infants in group C. Non-fatal relapse rates were similar in all three groups (12 [2%] infants in group A vs 13 [2%] infants in group B and 10 [1%] infants in group C). INTERPRETATION: Our results suggest that the two alternative antibiotic regimens for outpatient treatment of clinical signs of severe infection in young infants whose parents refused hospital admission are as efficacious as the standard regimen. This finding could increase treatment options in resource-poor settings when referral care is not available or acceptable.